Polymeric extended release systems for the treatment of dementia of the Alzheimer's type have been described. However, such extended release devices tend to be costly to manufacture and difficult to produce. In addition, they typically provide for once-daily oral administration. Thus, there still exists a need for improved methods of delivering such agents which maximize the medical benefits of the active agent, can be administered more conveniently at a dosing interval longer than 24 hours, and can be produced in a more cost effective manner.
The chemical structure of donepezil is:
The molecular weight of donepezil is 379.49, the melting point is 207° C., and the pKa is 9.1.
Donepezil has been successfully used in the treatment of dementia (a brain disorder that affects the ability to remember, think clearly, communicate, and perform daily activities and may cause changes in mood and personality) associated with Alzheimer's disease and is currently being marketed for that purpose. Such dementia patients are often non-compliant, making it difficult to assess whether or not a patient has received the proper dosage of medication. Applicants have discovered that it can be especially desired to formulate donepezil in a depot formulation or as an intramuscular formulation to assure consistent and proper dosage of the drug substance and to maximize the clinical benefits through improved patient compliance.
Donepezil is an organic weak base. In solution, it exists as the free base form at high pH (alkaline conditions). Aqueous solubility of donepezil increases with decreasing pH of the solution due to an increasing fraction of the drug being ionized. At high concentrations of the ionized drug (protonated amine), the solubility product of the salt (Ksp) will be exceeded and the salt form will precipitate out. The nature of the drug and counterion determine the Ksp and the associated solid state properties of the salt.
There are a wide range of counterions that have been used to prepare salts of bases using inorganic and organic acids. The most frequently used anion to form a salt of a basic drug is the hydrochloride form. For example, Aricept®, a commercial product of donepezil for oral administration, uses hydrochloride salt. Multiple organic salts of donepezil are also described in U.S. Patent Application Pub. No. 2008/0194628 by Mezei et al. These salts were prepared to improve stability, solubility or increased dissolution rate for oral administration. They possess desirable properties for immediate release dosage form. However, when extended release delivery of these salts are desired for a prolonged action, extended release technology using rate-controlling polymers are usually required as described in U.S. Patent Application Pub. No. 2011/0218216 by Vivek et al. and by P. Zhang et al, in Biomaterials (2007, 28(10):1882-8). In addition, such extended release devices tend to be costly to manufacture and difficult to produce at commercial scale. Thus, there still exists a need for improved methods of delivering such agents which maximize the medical benefits of the active agent, can be administered significantly less frequently than the current 24-hour dosing interval and can be produced in a more cost effective manner.
The chemical structure of pamoic acid is:
The molecular weight of pamoic acid is 388 g/mol, the pKa1 is 2.51, and pKa2 is 3.1.
It is known that the pH of muscle tissue can vary with exercise, stress, and injury which can affect drug solubility, and thus the rate of absorption of injectable drugs. Therefore, it is desirable to find an injectable extended release formulation in which the release rate of the active ingredient is minimally dependent on pH.